Molecular mechanisms of novel regulators in cytokine signal transduction

Xiaofei, Z.

By identifying and studying novel regulators, the studies described in this thesis give substantive insights into the molecular mechanisms and different levels of control of TGF-_/BMP, IL-1_ and Wnt signaling pathways. Crucially, our work for the first time demonstrated the monoubiquitination of an I-SMAD by an E2-E3 hybrid, and added an important unraveled mechanism of how monoubiquitination could affect TGF-_/BMP signaling. We found that UBE2O participates in IL-1R/TLR4-mediated NF-_B activation via a different mechanism than in BMP signaling. Future studies of ubiquitin enzymes will benefit from our model in chapter 3, which shows that UBE2O disrupts the interaction between TRAF6 and its upstream adapter MyD88 to limit polyubiquitination of TRAF6. Our studies in this thesis also added a new DUB to the list of deubiquitinases that can regulate IL-1R/TLR4 signaling, emphasizing the importance of controlling ubiquitination status in regulating NF-_B activation. Also, we reported a...Show moreBy identifying and studying novel regulators, the studies described in this thesis give substantive insights into the molecular mechanisms and different levels of control of TGF-_/BMP, IL-1_ and Wnt signaling pathways. Crucially, our work for the first time demonstrated the monoubiquitination of an I-SMAD by an E2-E3 hybrid, and added an important unraveled mechanism of how monoubiquitination could affect TGF-_/BMP signaling. We found that UBE2O participates in IL-1R/TLR4-mediated NF-_B activation via a different mechanism than in BMP signaling. Future studies of ubiquitin enzymes will benefit from our model in chapter 3, which shows that UBE2O disrupts the interaction between TRAF6 and its upstream adapter MyD88 to limit polyubiquitination of TRAF6. Our studies in this thesis also added a new DUB to the list of deubiquitinases that can regulate IL-1R/TLR4 signaling, emphasizing the importance of controlling ubiquitination status in regulating NF-_B activation. Also, we reported a new co-receptor for Wnt3a-induced signaling, suggesting compensating roles for co-receptors in the control of Wnt signaling. Therefore, the studies in this thesis yield more perception in understanding how TGF-_/BMP, IL-1R/TLR4 and Wnt signaling pathways can be regulated depending on the cell type, cell localization and cell state.Show less

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Molecular mechanisms of novel regulators in cytokine signal transduction

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